Currently there are no mechanism-based therapies available for autism spectrum disorders (ASDs) and intellectual disability (ID). The main barrier has been identifying the defective cellular processes within the brain that disrupt behavior and cognition. Increasing evidence indicates that many cases of ASD and ID have a genetic etiology. However, these genetic changes are numerous, often very rare, and remarkably diverse. One way to make sense of these findings is to assume that a plethora of gene mutations may similarly disrupt a common set of physiological processes that ultimately manifest behaviorally as ID and ASD. Testing this assumption is of paramount importance, as not only does it narrow the search for mechanisms of disease pathogenesis, but it also suggests therapeutic strategies that might apply broadly to an entire class of etiologies. Work on animal models of single-gene disorders associated with ID and ASD has supported the idea that one axis of pathophysiology is metabotropic glutamate receptor 5 (mGluR5) mediated synaptic protein synthesis and plasticity. In the animal model of fragile X syndrome (FX), mGluR5-mediated protein synthesis and plasticity in the hippocampus are exaggerated. Conversely, in the animal model of tuberous sclerosis complex (TSC), protein synthesis and plasticity downstream of mGluR5 are diminished. Of particular interest, inhibition of mGluR5 corrects cognitive (and many other) deficits in the FX model, whereas positive modulation of mGluR5 corrects cognitive defects in the TSC model. In the current work, we are asking if gene copy number variation at human chromosome 16p11.2, a polygenic cause of psychiatric illness that can include ID and ASD, similarly disrupts this core synaptic mechanism. This hypothesis is suggested by the findings that many genes in the affected region are predicted to be involved in protein synthesis regulation, and preliminary data in the mouse model of 16p11.2 microdeletion showing disrupted mGluR5-mediated synaptic plasticity and cognitive function, and correction of memory deficits by chronic inhibition of mGluR5. The specific aims of our proposed research are to (a) further characterize the state of synaptic transmission and plasticity in the hippocampus of 16p11.2 CNV model mice, (b) characterize synaptic protein synthesis and the molecular signaling pathways which may be disrupted in these mice, (c) further assess the behavioral deficits in 16p11.2 CNV model mice, and (d) attempt to correct memory deficits with rational pharmacotherapies previously validated in animal models of FX and TSC.